Sleep apnea is a common disorder associated with an increased risk of cardiovascular disease, and is particularly prevalent in heart failure patients. The cardiovascular risk of sleep apnea is likely to be amplified in the presence of heart failure since each disorder can aggravate the other. This proposal examines the interrelationship between sleep apnea and heart failure, and the mechanisms leading to cardiovascular stress when the two interact. Our proposal is predicated on the notion that sleep apnea increases cardiovascular stress, and further worsens left ventricular function in heart failure patients. Our major hypothesis is that a reciprocal interaction exists between sleep apnea and heart failure, wherein sleep-related disturbances in key mediators lead to acute and chronic increases in cardiovascular stress and worsening left ventricular function. To test this hypothesis, experiments are proposed in humans and murine models of sleep apnea and heart failure. In Specific Aims 1 and 2, heart failure patients will be intensively studied nocturnally to elucidate the mechanisms by which sleep apnea and its associated arousals and hypoxemic episodes increase cardiovascular stress acutely and perpetuate cardiovascular stress chronically. In Specific Aims 3 and 4, studies in novel murine models of chronic intermittent and sleep-induced hypoxia will examine the mechanisms in which sleep apnea and heart failure interact at the cardiac and central nervous system level. This potentially harmful interaction will be explored by assessing responses in: (a) novel mediators of cardiovascular stress (reactive oxygen species, cytokines, leptin, and insulin), (b) an important biomarker of acute and chronic cardiovascular stress (B-type natriuretic peptide, BNP), (c) cardiac tissue, and in (d) cardiac and CNS gene expression. The research plan will elucidate new mechanisms causing excess cardiovascular morbidity and mortality in heart failure, as well as provide new approaches to detect, monitor and treat sleep apnea in heart failure patients.